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Re-functionalization of 9-Substituted Isocolchicides via Nucleophilic 7e/e-Substitution. A General Synthesis of ll-Alkyl(Aryl)thioisocolchicidesM arino Cavazza3, Francesco P ietra5a Dipartimento di Chimica e Chimica Industriale, Universitä di Pisa, 56126 Pisa, Italy b Istituto di Chimica, Universitä di Trento, 38050 Povo-Trento, ItalyZ. Naturforsch. 51b, 1347-1351 (1996); received May 8, 1996Alkyl(aryl)thioisocolchicides, Functionalization, Tele- vs. /pso-Substitution,Activation by Alkylthio Group, NMR Spectra
9-Substituted isocolchicides in methanol or dimethyl sulfoxide undergo /pso-substitution by sodium thiolates in mixture with the corresponding thiols, giving 9-alkyl(aryl)thio-substituted isocolchicides which are prone to in situ re/e-substitution affording ll-alkyl(aryl)thio func- tionalized isocolchicides. Such C -ll activation by dicoordinated sulfur is used here for a general synthesis of 1 l-alkyl(aryl)thioisocolchicides.
Introduction
D espite keen in terest in colchicine and its derivatives (colchicinoids) by chemists, biologists and pharmacologists, very little is know n about the 11- substituted isocolchicide series. U ntil recently, only two m em bers of this series were known, i.e. 11-methylthio- [1,2] and 11-amino-isocolchicide [3]. The way they are form ed is interesting: re-exam ination of Velluz’s reaction of isocolchicine with sodium m ethanethiolate to give 11-methylthi- oisocolchicide [1,2] led us to establish that this com pound is form ed via initial ipso replacem ent of the m ethoxy group of isocolchicine by the thio- late to give 9-methylthioisocolchicide (1); the la tter undergoes re/e-substitution at C - l l by the thio- late [4]. This is in keeping with general rules concerning electron acceptance by dicoordinated sulfur at C-9 in simple troponoids [5]. On this basis, we recently succeeded in the C - l l refunction- alization of 9-substituted isocolchicides by prim ary or secondary amines: isocolchicides carrying a C- 9 activating nucleofugic group like SCH 3, SO C H , or Cl were found to undergo re/e-substitution at C - ll by the amine in dimethyl sulfoxide in com petition with /pso-substitution at C-9 [6]. Thus, on treating 1 in dim ethyl sulfoxide at 64°C with excess amine, ca. 1:1 m ixtures of 9- and 11-amino
* Reprint requests to Prof. M. Cavazza.
substituted isocolchicides were obtained, including11-piperidino [6], -11-morpholino- [7] and 11 -n- propylaminoisocolchicide [7], H ere we present an extension of the above m ethodology leading to a general synthesis of 1 l-alkyl(aryl)thioiso- colchicides.
Results and Discussion
Treatm ent of 1 or 9-tosylisocolchicide (2) with m ethanol containing ca. 35 mol. equiv. of in situ prepared sodium thiolate, led to m ixtures of 9-sub- stituted and 11-substituted isocolchicides that were collected and separated by Thin-Layer C hrom atography after that the reaction m ixtures were left for 20 h at room tem perature (Schem e 1 and Table I). Similar results were obtained by addition of ca. 35 mol. equiv. of sodium thiolate and 1.2 mol. equiv. of thiol to solutions of 1 or 2 in dimethyl sulfoxide (Schem el). Com parison of these thiolate reactions with those of the same substrates with amines reveals interesting differences. Thus, while for the am ine reactions it is necessary to start with a substrate that, like 1, carries an activating (i.e. re/e-directing) C-9 substituent, there is no such a need for the thiolate reactions: the more easily accessible tosylate 2 [8] proved to be quite convenient, undergoing fast irreversible ipso substitution by the thiolate to give corresponding 9- alkyl(aryl)thioisocolchicide that takes part to equilibria leading to the re/e-substitution product (Scheme 2). However, unlike in reactions with pri-
0932-0776/96/0900-1347 $06.00 © 1996 Verlag der Zeitschrift für Naturforschung. All rights reserved. D
1348 M. C avazza-F . Pietra • Re-functionalization of 9-Substituted Isocolchicides
RSNa/MeOH -------------- ►
RSNa/RSH/DMSO
X=OTS468
10
R=Bu
R=i-Pr
R=HOC2H4
R=Ph Scheme 1.
RS'
X=SMe or OTs
base H+
RS
RS1 \ H+f )
~-RS- I. L b baseH~ F \
RSSR RS r T *
Scheme 2.
Thiolate zpso-Substitutionproduct
Yield (%) te/e-Substitutionproduct
Yield (%)
BuSNa 3 43 4 42i-PrSNa 5 51 6 14HO(CH,),SNa 7 55 8 20PhSNa 9 48 10 32
Table I. Product-yield in the preparative reactions carried out with 1 or 2 and excess thiolate in MeOH at room temperature.
M. C avazza-F . Pietra • R e-functionalization of 9-Substituted Isocolchicides 1349
mary or secondary amines, which act both as nucleophiles and protonating agents [9] in reactions with thiolates in aprotic dim ethyl sulfoxide an extra source of protons is needed: a slight excess of free thiol was added to establish the protonation equilibria (Scheme 2). In the absence of free thiol, only /pso-substitution was observed. A lthough in some cases, e.g. with sodium /so-propanthiolate (Table I), a low tele/ipso ratio of products was observed, we are not aware about any o ther route to 1 l-alkyl(aryl)thio-substituted isocolchicides.
Experim ental
General
'H N M R and l3C N M R spectra were obtained with a Gem ini Varian BB spectrom eter 200 MHz, in C D C I 3 as the solvent, unless otherwise stated, TMS as an internal standard. Mass spectra (E l) were taken with a K ratos MS80 spectrom eter with a hom e-built com puterized acquisition system. M elting points were obtained with Reichert Therm ovar apparatus and are uncorrected.
Materials
C H 3O H ( RS C. E rba) was used as such. DM SO (C. E rba) was distilled from C aH 2 under A r and stored over 3 A m olecular sieves. 9-methylthioiso- colchicide 1 [4] and 9-tosyloxyisocochicide 2 [8] were prepared according to known procedures.
General Procedure
To a stirred solution obtained from Na (0.052g,2.26 mm ol) and dry M eO H (6 ml), were added, under argon, 2.8 mmol of thiol followed by 0.065 mmol of either 1 or 2. The m ixture was left for 20 h at room tem perature, evaporated under vacuum, and then w ater was added and the resulting suspension was extracted with CHC13. The residue from evaporation of the organic phase was subjected to TLC, eluent C H C l3/acetone 3:2, collecting 9-substituted and 11-substituted isocolchicides at the Rf values indicated below and with the yields reported in Table I.
C orrespondig reactions were carried out by adding to 0.05 mmol of e ither 1 or 2 in dried DMSO, under argon, 1.6 mmol of sodium thiolate followed by 0.06 mmol of thiol. These m ixtures were w orked up as for reactions in M eOH.
(S)-N-(5,6,7,10- Tetrahydro-1,2,3-trimeth oxy -9-butylthio-10-oxobenzo[a]heptalen-7-yl)acetamide(3)'
Yellow solid, Rf=0Al, m.p. 221-223°C dec.'H NMR: (3= 0!93 (3H, t, 7=7.2, C / / ,C 3H 6), 1.50
(2H, m, CH^CH 2C2H 4), 1.73 (2H, m, C 2H ,C / / 2 C H t), 2.05 (3H, s, Ac), 2 .55-2 .2 (4H, series of m,6-H and 5-H), 2.87 (2H, m, S C //2C ,H 7), 3.92, 3.89, 3.66 (3 x 3H, s, for the 3 M eO ), 4.60 (1H, td, 712.5, 6.3, 7-H), 6.56 (1H, s, 4-H), 7.41 and 6.97 [2H, AB system, 7(AB)=12.5, 11-H and 12-H], 7.40 (1H, s, 8-H).
13C NMR: 0=182.33, 169.83, 157.08, 153.78, 143.55, 141.10, 136.63, 134.82, 131.43, 125.89, 124.47, 107.43, 61.60, 61.50, 56.17, 52.95, 38.49, 31.73, 29.94, 29.75, 29.56, 22.95, 22.45, 13.78.
UV Amax(M eOH)/nrn = 260, 290,362,383,402sh.MS m/z (% ) : 457 (13, M + ), 398 (19).HRM S m/z obs: 457.19177 (M + ), calc, for
C ,sH 3,O sNS: 457.19229.
(S)-N- (5,6,7,10- Tetrahydro-1,2,3-trimethoxy-l 1 - butylthio-10-oxobenzo[aJheptalen-7-yl)acetamide(4)
Yellow solid, /?/=0.73, m.p. 95-96°C .'H NMR: 6=0.91 (3H, t, 7=7.16, C Z /^ H * ) , 1.45
(2H, m, C H 3CH2 C2H 4) 1.70 (2H, m, C2H , CH2CH 2) 2.04 (3H, s, A c), 2 .60-2 .20 (4H, series of m, 6-H and 5-H), 2.80 (2H, m, S C //2C 3H 7), 3.93,3.90, 3.67 (3x3H,s,for the 3 M eO), 4.55 (1H, td, 7=12.5, 6.3, 7-H), 6.58 (1H, s, 4-H), 7.44 and 7.06 [2H, AB system, 7(A B)= 12.5, H -8 and H-9], 7.33 (1 H,s, H-12).
13C NM R: <3=182.44, 170.01, 155.08, 153.93,151.03, 141.19, 139.29, 135.25,133.20, 132.82, 132.69, 126.51, 107.56, 61.77, 61.47, 56.15, 51.93,38.43, 31.12, 31.02, 30.06, 29.80, 23.09, 22.33, 13.68.
UV Amax(M eOH)/nrn: 267, 330, 402sh.MS m/z (% ) : 457 (15, M + ), 398 (21).HRM S m/z obs: 457.19234 (M + ), calc, for
C25H 310 5NS: 457.19229.
(5)-N-(5,6,7,10- Tetrahydro-1,2,3-trimethoxy-9-i-propylthio-10-oxobenzo[a]heptalen-7-yl)- acetamide (5)
Yellow solid, Rf=0.60, m.p. 126-127°C.'H NMR: 6 = 1.44 (6H, d, 7= 6.7, (C /Z ^ C H ),
2.04 (3H, s,AC), 2 .60-2 .20 (4H, series of m, 6-H and 5-H), 3.42 (1H, heptet, 7=6.7, M e2C //S ), 3.94,3.90, 3.69 (3x3H, s, for the 3 M eO ), 4.60 (1H, td, 7= 12.0, 4.4, 7-H), 6.20 ( 1H, d, 7=4.4, N H ), 6.56 (1H, s,4-H), 7.41 and 6.98 [2H, AB system, 7(A B )= 12.5, H - l l and H-12], 7.40 (1H, s, H -8 ). 13C NM R: 0=
1350 M. C avazza-F . Pietra • Re-functionalization of 9-Substituted Isocolchicides
181.20, 169.58, 142.88, 140.75, 136.76, 134.72,132.04, 132.00, 125.11, 107.50, 107.46, 60. 08, 56.21,56.16, 52.94, 38.65, 34.91, 30.09, 29.99, 29.91, 29.75,23.02, 22.28, 22.09.
UV Amax(M eO H )/nm : 260, 290, 363, 386, 402sh. MS m/z (% ) : 443 (11, M + ), 384 (35).H RM S m/z obs: 443.17608 (M +), calc, for
C24H 29O 5NS: 443.17664.
(S)-N-(5,6,7,10-Tetrahydro-l ,2,3-trimeth oxy -1 l-i-propylthio-10-oxobenzo[a]heptalen-7-yl)- acetamide (6 )
Gum m y yellow solid, Rf=0A2.'H N M R d=1.42 (6H, d, 7=6.7, (CH3)2CH), 2.04
(3H, s, Ac), 2 .60-2 .20 (4H, series of m, 6 -H and 5-H), 3.33 (1H, heptet, 7=6.7, M e2C //S ), 3.94, 3.91, 3.68 (3x3H, s, for the 3 M eO ), 4.55 (1H, td, 7=12,5.2, 7-H), 5.95 (1H, d, 7=5.2, N H ), 6.58 (1H, s, 4- H), 7.32 and 7.07 [2H, AB system, 7(A B)= 12.0, H -8 and H-9], 7.37 (1H, s, H-12).
U V Amax(M eO H )/nm : 267, 332, 402sh.MS m/z (% ) : 443 (14, M + ), 384 (38).H RM S m/z obs: 443.17610 (M + ), calc, for
C 24H 290 5N S : 443.17664.
(S)-N-(5,6,7,10-Tetrahydro-1,2,3-trimethoxy-9-(2' - hydroxyethylthio)-10 -oxobenzo[aJheptalen-7-yl)- acetamide (7)
Yellow solid, ^ = 0 .1 8 , m.p. 115-117°C.'H NM R: (3= 2.07 (3H, s, Ac), 2 .60-2.20 (4H,
series of m, 6 -H and 5-H), 3.14 (2H, t, S C f/2C H 2O H ), 3,90 (2H, t, H O C //2C H 2S), 3.92,3.90, 3.67 (3x3H, s, for the 3 M eO ), 4.61 (1H, m,7-H), 6.57 (1H, s, 4-H), 7.47 and 6.98 [2H, AB system, 7(AB)=12.5, H - l l and H-12], 7.66 (1H, s, H- 8), 7.95 (1H, br signal, NH).
13C NM R: (3=182.51, 170.78, 155.92, 154.00, 150.97, 145.11, 145.06, 141.92, 137.78, 135.12,131.21, 125.85, 125.62, 107.63, 61.65, 61.58, 61.48,61.44, 60.21, 56.17, 52.98, 38.28, 34.29, 30.07, 22.90.
U V Amax(M eO H )/nm : 260, 290, 383, 402sh.MS m/z (%) : 445 (2, M + ), 385 (73).H RM S m/z obs. : 445.15500 (M +), calc, for
C23H 270 6NS: 445.15591.
(S)-N-(5,6,7,10-Tetrahydro-1,2,3- trim eth oxy -11- (2'-hydroxy ethylthio )-10-oxobenzo[a Jhep taten - 7- yl)acetamide (8 )
Yellow solid, 7?y=0.16, m.p. 127-130°C.'H NM R: (3=2.04 (3H, s, Ac), 2 .60-2.20 (4H,
series of m, 6-H and 5-H), 3.06 (2H, t, 7=6.5, S C //2C H ,O H ), 3.90 (2H, t ,H O C //2CH ,S), 3.94, 3.92, 3.69 (3x3H, s, for the 3 M eO ), 4.54 (1H, td.
7= 12.0 , 6.2, 7-H), 5.98 (1H, d, 7=6.2, N H), 6.59 (1H, s, 4-H), 7.36 and 7.09 [2H, AB system, 7(AB)=12.5, 8-H and 9-H], 7.38 (lH ,s, 12-H).
13C NMR: (3=181.50, 170.00, 154.20, 154.00, 153.40, 141.34, 133.92, 133.38, 132.18, 107.94, 107.85, 107.81, 62.20, 62.00, 60.13, 56.30, 56.24, 56.17, 52.06, 38.59, 34.28, 31.00, 29.99, 23.13.
UV Amax(M eOH)/nrn: 370, 331, 401sh.MS m/z (% ) : 445 (1.5, M + ), 385 (33).HRM S m/z obs.: 445.15502 (M + ), calc, for
C23H 270 6NS : 445.15591.
(S)-N- (5,6,7, / 0- Tetrahydro-1,2,3-trimethoxy- 9-phenylthio-l 0-oxobenzofa ]heptalen-7-yl) - acetamide (9)
Yellow solid, R f=0.64, m.p. 154-155°C.>H NMR: (3=2.17 (3H, s, A c), 2 .50-2.10 (4H,
series of m, 6-H and 5-H), 3.92, 3.87, 3.65 (3x3H, s, for the 3 M eO ), 4.41 (1H, td, 7=12.7, 6.5, 7-H),5.2 (1H, d, 7=6.7, N H ), 6.52 (1H, s, 4-H), 6.93 (1H, s, 8-H), 7.43 and 7.05 [2H, AB system, 7(A B)=12.5, 12-H and 11-H], 7.52 (3H, m, phenyl), 7.63 (2H, m, phenyl).
13C NMR: 0=181.33, 169.31, 158.50, 153.82,143.02, 141.14, 136.48, 134.75, 132.42, 131.86, 130.18, 129.84, 125.30, 125.22,107.47,107.41, 61.68, 61.60, 61.51, 61.45, 56.15, 52.33, 38.66, 29.80, 23.02.
UV Amax(M eO H )/nm : 258, 360, 383, 401sh.MS m/z (% ) : 477 (14, M + ), 449 (17, M -CO),
390 (14).HRM S m/z obs. : 477.15970 (M + ), calc, for
C27H 270 5NS : 477.16099.
(S)-N-(5,6,7,10-Tetrahydro-l,2,3-trimethoxy-11 -phenylthio-10-oxobenzo [a] heptalen-7-yl)- acetamide (10)
Yellow solid, Rf= 0.35, m.p. 117-119°C.'H N M R (C D 3C O C D 3): ö =1.90 (3H, s, Ac),
2.60-2.10 (4H, series of m, 6-H and 5-H), 3.82, 3.68, 3.52 (3x3H, s, for the 3 M eO ), 4.36 (1H, td, 7=12.2, 6.2, 7-H), 6.67 (1H, s, 4-H ), 6.89 (1H, s, 12- H), 7.56 and 7.00 [2H, AB system, 7(AB)=12.6, 9- H and 8-H], 7.76 (1H, d, 7=6.2, N H ), 7.59-7.45 (5H, m, phenyl).
13C NMR: (3=181.59, 169.86, 156.15, 153.73, 141.77, 139.43, 136.34, 136.23, 134.91, 134.58, 134.49, 134.06, 132.85, 130.55, 129.73, 129.52,126.16, 107.24, 107.09, 61.40, 61.13, 56.07, 52.02, 38.57, 29.99, 29.75, 23.11.
UV 2max(M eO H )/nm : 268, 331, 380, 400sh.MS m/z (% ) : 477 (21, M + ), 449 (24, M -CO),
390 (19).HRM S m/z obs.: 477. 16043 (M + ), calc, for
C27H ,7OsNS: 477.16099.
M. C avazza-F . P ietra • R e-functionalization of 9-Substituted Isocolchicides 1351
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